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Age-Specific Onset and Distribution of the Natural Anticoagulant Deficiency in Pediatric Thromboembolism

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Age-Specific Onset and Distribution of the Natural Anticoagulant Deficiency in Pediatric Thromboembolism nature publishing group Clinical Investigation Articles Age-specific onset and distribution of the natural anticoagulant deficiency in pediatric thromboembolism Masako Ichiyama1, Shouichi Ohga2, Masayuki Ochiai1, Koichi Tanaka1, Yuka Matsunaga1, Takeshi Kusuda1, Hirosuke Inoue1, Masataka Ishimura3, Tomohito Takimoto3, Yui Koga4, Taeko Hotta4, Dongchon Kang4 and Toshiro Hara1,3 BACKGROUND: The early diagnosis of inherited throm- protein S (PS), and antithrombin (AT) deficiency, as well as bophilia in children is challenging because of the rarity and factor V G1691A (FVL) and prothrombin G20210A (FII) hemostatic maturation. variants (4). The high incidence of VTE in Caucasians (5) is METHODS: We explored protein C (PC), protein S (PS), explained by the fact that FVL and FII G20210A carriers were and antithrombin (AT) deficiencies in 306 thromboembolic found in 20–60% of adult VTE patients in Caucasian but not patients aged ≤20 y using the screening of plasma activity and Asian ancestries (6–9). PC, PS, and AT deficiencies share the genetic analysis. lower prevalence than FVL and/or FII G20210A carriers, but RESULTS: Reduced activities were determined in 122 patients the higher risk of the first and recurrent VTE than the other (40%). Low PC patients were most frequently found in the low- thrombophilias. On the other hand, the diagnosis is challeng- est age group (0–2 y, 45%), while low PS or low AT patients ing during infancy and early childhood, because the references were found in the highest age group (16–20 y; PS: 30% and of increasing anticoagulant activity range widely until ado- AT: 20%). Genetic study was completed in 62 patients hav- lescence (10,11). The true effect of the natural anticoagulant ing no other causes of thromboembolism. Mutations were deficiencies on the development of pediatric thromboembo- determined in 18 patients (8 PC, 8 PS, and 2 AT genes). Six of lism remains elusive because of the rare occurrence and the eight patients with PC gene mutation were found in age 0–2 y elaborative genetic screenings. (75%), while six of eight patients with PS gene mutation were To clarify the clinical impact of the inherited deficiency of in 7–20 y. Two AT gene–mutated patients were older than 4 y. natural anticoagulant on children, we conducted the genetic Four PC-deficient and two PS-deficient patients carried com- analysis of PC, PS, and AT deficiency after the screening of pound heterozygous mutations. All but one PC gene–mutated each activity for pediatric patients with thromboembolism patient suffered from intracranial thromboembolism, while over 20 y in a single institution. The results demonstrated the PS/AT gene–mutated patients mostly developed extracranial distinct presentation of PC and PS deficiencies in infants and venous thromboembolism. children, respectively, reflecting the genotype of adult Japanese CONCLUSION: Stroke in low PC infants and deep vein throm- patients. bosis in low PS/AT school age children could be targeted for genetic screening of pediatric thrombophilias. RESULTS Distribution of Thromboembolic Patients Of 306 patients aged ≤20 y (male: female 1:1.14), 186 suffered hromboembolism is a multifactorial disease involving from intracranial lesions including ischemic and/or hemor- Tgenetic predispositions, underlying disorders, and var- rhagic strokes. The extracranial lesions consisted of renal vein ied triggers including infection or injury. Vascular, circula- thrombosis (n = 7), purpura fulminans (n = 3), deep vein tory, and hemostatic conditions are distinctively associated thrombosis in the leg (n = 15), and pulmonary thromboembo- with the development of arterial and venous thromboses. lism (n = 9). Patients younger than 3 y were 27% of all patients. Thromboembolism, formerly recognized as a rare event in The largest age group was <1 y of age (n = 50, 16.3%), and the children (1), has been increasingly diagnosed as a complica- number of other age groups were similar (median: 12, ranging: tion of sepsis, cancer, cardiovascular disease, and therapy- 9–17 (3.0–5.5%)). related events. Recent advances in the intensive cares, cardiac surgery, and transplantation medicine along with the imaging PC, PS, and AT Activities in Patients diagnosis may contribute to the increased number of pediatric A total of 122 patients had the reduced activity of either anti- patients with thrombosis (2,3). The established genetic risks coagulant; 95 with low PC (31%), 48 with low PS (16%), and 20 of venous thromboembolism (VTE) include protein C (PC), patients with low AT activity (7%; Figure 1). Low PC patients 1Comprehensive Maternity and Perinatal Care Center, Kyushu University Hospital, Fukuoka, Japan; 2Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan; 3Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 4Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Hospital, Fukuoka, Japan. Correspondence: Shouichi Ohga ([email protected]) Received 5 March 2015; accepted 29 June 2015; advance online publication 14 October 2015. doi:10.1038/pr.2015.180 Copyright © 2016 International Pediatric Research Foundation, Inc. Volume 79 | Number 1 | January 2016 Pediatric REsEarcH 81 Articles Ichiyama et al. were most frequently determined in the lowest age group (0–2 Mutations of PC, PS, and AT Genes in Patients y, 45%), while low PS or low AT patients were frequently found Of 62 children who showed the low level of at least one factor,­ in the highest age group (16–20 y; PS: 30% and AT: 20%). The mutation carriers were found in low PC (n = 8/39, 21%), PS number of patients with low activity in age groups are shown (n = 8/27, 30%), or AT (n = 2/5, 40%) patients, respectively. in Figure 2. The proportions of low PC patients were higher Forty-four patients carried no mutations. Age distribution than those of low PS or AT patients in age 0–2 (each <0.00001) of 62 patients differed among three deficiencies (0.0042; and 13–15 y (0.0001, 0.0155), respectively. The proportion of Figure 3). The proportion of age 0–2 y patients with PC defi- low PC or PS patients (19%) was each higher than that of low ciency (44%) was the highest among any age group patients AT patients in 7–12 y (0.0005). The number of patients show- with PS or AT deficiency. Six of eight patients with PC gene ing both low levels of PC and PS activities were 25 (20%), 5 of mutations (75%) were found in the age group 0–2 y, in which whom had the low levels of all three factors (Supplementary only two PS and no AT mutation carriers were determined. Figure S1 online). Four of eight patients with PS gene mutations (50%) were found in the age group 7–12 y. No ratio of mutated to analyzed patients differed in the age-groups. Thromboembolism (June 1993–March 2012) Clinical Onset, Genotype, and Activity Levels of PC, PS, and AT in 1,867 patients 1,561 patients age ≥ 21 y, the Mutation Carriers Anomaly, inborn errors of metabolism Eighteen patients with a mutation are listed in Table 1. Seven 306 patients 16.4%, age 0–20 y out of eight PC-deficient patients suffered from intracranial Low plasma activity thromboembolism and five of them were younger than 2 y. On PC PS AT Normal activities of PC, PS, and AT: 184 the other hand, six of eight PS-deficient patients presented in 122 patients 95 48 20 the second decade of life, the onset of which were adult type Acquired thrombosis (including APS): 60 deep vein thrombosis of pulmonary thromboembolism in five of them. Double allele (homozygous or compound het- 39 27 5 62 patients erozygous) and one allele (heterozygous) mutation(s) were Genetic study 31 19 3 found in half of eight PC-deficient patients, respectively. On 44 patients No mutation the other hand, double allele mutated patients were only two 882 Mutation of eight heritable PS-deficient patients, both of whom carried PS-Tokushima. Two other patients had PS-Tokushima. Both Figure 1. Flowchart of the genetic study of pediatric thrombophilia in patients with heritable AT deficiency carried heterozygote AT a Japanese institution. During the 20 y, 306 patients (≤20 y of age) were mutation. Four of eight patients with PC gene mutation and screened by the plasma activities of protein C (PC), protein S (PS), and anti- thrombin (AT) and underwent the genetic study if they have idiopathic or * unusual thrombophilic predispositions. ns ** ns Number of ‡ ns † ns patients ** ‡nsnsnsnsnsnsns 100 ** * PC deficiency 80 PS deficiency 60 1 6 1 AT deficiency Mutation 2 2 40 Mutation 4 Mutation 1 1 20 0 n = 39 n = 27 n = 5 PC PS AT PC PS AT PC PS AT PC PS AT PC PS AT 0–2 3–6 7–12 13–15 16–20 Figure 3. Age distribution of patients with thromboembolism carrying PC, PS, and AT gene mutation. The circle size represents the number of Figure 2. Proportion of patients who showed the low plasma activity of patients. (a) PC deficiency (n = 39): 0–2 y, 44%; 3–6 y, 13%; 7–12 y, 8%; PC, PS, and AT according to the age groups. 0–2 y: infants (n = 84; low PC, 13–15 y, 23%; and 16–20 y, 13%. Six of eight patients with PC gene muta- 45%; low PS, 8%; low AT, 5%), 3–6 y: preschoolers (n = 53; low PC, 14%; tions (75%) were found in the age group 0–2 y. (b) PS deficiency (n = 27): low PS, 8%; low AT, 4%), 7–12 y: elementary school children (n = 73; low 0–2 y, 15%; 3–6 y, 15%; 7–12 y, 33%; 13–15 y, 4%; and 16–20 y, 33%. Four of PC, 19%; low PS, 19%; low AT, 1%), 13–15 y: junior high school students eight (50%) patients were found in the age group 7–12 y.
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